The present invention relates to a new controlled release delivery system using melt spun biodegradable polymers as a carrier or host material for a bio-effecting agent such as a pharmaceutical active or a hormonal compound.
The convenience of administering a single dose of a medication which releases active ingredients in a controlled fashion over an extended period of time as opposed to the administration of a number of single doses at regular intervals has long been recognized in the pharmaceutical arts. The advantage to the patient and clinician in having consistent and uniform blood levels of medication over an extended period of time are likewise recognized. The advantages of a variety of controlled or sustained release dosage forms are well known. Among the most important advantages are: (1) increased contact time for the drug to allow for local activity in the stomach, intestine or other locus of activity; (2) increased and more efficient absorption for drugs which have specific absorption sites; (3) the ability to reduce the number of dosages per period of time; (4) employment of less total drug; (5) minimization or elimination of local and/or systemic side effects; (6) minimization of drug accumulation associated with chronic dosage; (7) improved efficiency and safety of treatment; (8) reduced fluctuation of drug level; and (9) better patient compliance with overall disease management.
Additionally, many experts believe sustained release drug delivery has many important non-therapeutic ramifications as well, including a financial saving to the patient in terms of less lost work days, less hospitalization and fewer visits to the physician.
It is known that certain design parameters are critical to proper drug delivery. Typically, they are: (1) delivering the drug to the target tissue; (2) supplying the drug in the correct temporal pattern for a predetermined period of time and (3) fabricating a delivery system that provides drug in the desired spatial and temporal pattern. Controlled or sustained release drug delivery systems are intended to manipulate these parameters to achieve the aforementioned advantages when compared to conventional pharmaceutical dosing.
Controlled release of actives has conventionally focused on oral dosage forms such as tablets and capsules, where release of the active was accomplished by diffusion through or erosion of the matrix. Conventional formulations use waxes or hydrophilic gums as the primary drug carriers to prolong the release of the active. In wax formulations, the drug is dispersed in the wax matrix in a molten state. This method has the disadvantage of possible decomposition and/or crystalline formation of the drug, rendering it less active or effective as a therapeutic agent. Other systems using polymeric coatings or laminates on the tablets to delay tablet disintegration and protect the active from prematurely releasing in the stomach where gastric secretions would destroy its activity. Still other systems use water-swellable hydrogel matrices to control the release of the agent by surface-to-center swelling of the matrix and subsequent diffusion of the agent. For common methods of producing controlled release products, see Sustained And Controlled Release Drug Delivery Systems, Robinson, Joseph R., Ed. pp 138-171, 1978, Marcel Dekker, Inc. N.Y., N.Y.
More recently, the use of biodegradable polymers as matrices or carriers for drugs has become more prevalent. For example, the use of biodegradable articles, such as dispensing vehicles, which are implanted in the animal, are intended to be broken down or degraded by the animal body into residues or moieties which are absorbed, metabolized or otherwise naturally removed by the body. Early forms of these implantable polymeric devices are exemplified in U.S. Pat. No. 3,882,699, which discloses a drug dispersed in a biodegradable polymeric material and shaped into a solid shape. This patent requires the use of low crystalline lactic acid polymers in order to obtain faster release of drug. Solvents are used to form homogeneous solutions of the drug/polymer mixture and extrusion, molding or compaction techniques are used to form the product.
Numerous drug delivery systems using polymers which are bio-eroding in the body are disclosed. For example, U.S. Pat. Nos. 4,888,176, 4,891,225, 4,757,128, 4,093,709 disclose the use of polyanhydrides, poly(othoesters) and poly(orthocarbonates) to make articles for delivering agents. These patents and others deal with biodegradable synthetic polymers as drug matrices for controlled release of the drug over a sustained period of time. These delivery systems are manufactured using conventional solvent casting, extrusion or molding techniques to physically entrap the drug in the polymer matrix. Solvent casting involves preparing a solution of drug and polymer using a solvent and removing the solvent to leave a residue of polymer and drug presumably in intimate physical contact. The residue can then be further processed or shaped using conventional thermoplastic processing methods.
Another conventional thermoplastic processing technique involves the use of melt-spinning techniques. For example, U.S. Pat. No 4,335,232 to Irwin discloses melt-spinning aromatic copolyesters; and U.S. Pat. No. 4,072,658 to Okamato, et al. discloses melt-spinning of polystyrene. These conventional melt-spinning techniques involve subjecting a feedstock to sustained heat treatment and are described in F. Billmeyer, Jr., Textbook Of Polymer Science, 518-522 (Wiley International Edition 2d). Conventional spinning processes require melting the polymer or dissolving the polymer in solution (an exception is the aqueous dispersion of a polymer, such as polytetrafluoroethylene), followed by removal of the liquid and sintering. In these melt-spinning procedures, molten polymer is pumped at a constant rate under high pressure through a plate having a number of small holes, which is referred to as a spinneret. Polymer is melted, usually by contacting it with a hot grid or by use of an extrusion-type screw, and passed directly to a meter pump. Filaments emerge from the spinnaret into air where it begins to cool. As the fibers solidify, they are brought together and drawn to orient the fibers. In both dry spinning and wet spinning procedures, the polymer or polymer derivative is put into solution prior to forming the fiber.
All of the conventional thermoplastic processing techniques when applied to drugs and other active agents suffer from a number of obvious drawbacks. Processing temperatures encountered in the polymeric melt stage vary with the type of polymer and are often too high to retain stability of the drug. Drug/polymer interactions or degradation of the drug may occur, rendering the drug inactive or less effective for its intended purpose. Biodegradable polymers such as polyanhydrides require higher molecular weights in order to avoid brittleness during solvent casting and maintain their structural integrity in the resultant products.
The literature discloses that release of drugs from polymer systems is dependent upon a number of factors. One critical factor is the degree of crystallinity present in the polymer. The higher the degree of crystallinity, the slower the rate of degradation of the polymer and thus the slower the release of drug or active from the polymer matrix. Conversely, polymers with less crystallinity generally degrade more easily or rapidly, thereby effectuating release of the active in a shorter time. For a discussion of the effect of polymer crystallinity on drug release see "Using Biodegradable Polymers In Advanced Drug Delivery Systems", Schacht, Etiens 41, Medical Device Technology, January-February 1990; and Flory, Paul J., Principles Of Polymer Chemistry, 5th Ed., 1966. The concern regarding crystallinity has been addressed by attempting to balance the molecular weight of the polymer with its crystalline structure to obtain the desired release rate and duration. The conventional processing techniques have not afforded practical, reproducable and cost effective methods for solving this concern.
More recently, a new method of producing substances having pharmacological properties was disclosed in U.S. Pat. No. 4,855,326. This patent discloses combining sugar with a medicament and spinning the combination into a readily water-soluble floss or fiber. In U.S. Pat. No. 5,011,532, the disclosure deals with oleaginous substances such as vegetable oil, baby oil, margarine, lanolin, cocoa butter and the like, and how their lack of affinity for water is altered by mixing the oleaginous substance with sugar and melt-spinning the mixture in cotton candy spinning machines or the equivalent. As so modified, the products disperse in water forming a colloidal or pseudocolloidal dispersion.
Other disclosures which relate to spinning substances with one or more sugars are found in U.S. Pat. No. 4,873,085 issued Oct. 10, 1989, U.S. Pat. No. 5,034,421 issued Jul. 23, 1991, U.S. Pat. No. 5,028,632 issued Jul. 2, 1991, and U.S. Pat. No. 4,997,856 issued Mar. 5, 1991. The products described in the above-mentioned patents and applications are all produced by processing in a cotton candy machine. Illustrative of a cotton candy machine is the Econo Floss Model 3017 manufactured by Gold Medal Products Co. of Cincinnati, Ohio. The process described in the above-identified disclosures involve the use of sugar(s) as a feedstock material which is spun to produce a material such as a floss, fiber, and the like. Accordingly, the technology described in the above-identified disclosures relies on the physical characteristics of sugar.
It is apparent that a need exists for a controlled release composition for delivering bio-effecting actives such as therapeutic and prophylactic agents to animals which are based on biodegradable non-saccharide polymer carriers which can be made without the disadvantages associated with conventional thermoplastic processing and which are capable of controllably releasing the active over a pre-determined period of time at a chosen rate. The present invention provides such a composition, and offers an efficient and cost effective method of preparation.